The relationship among genetic control, cellular calcium (Ca) metabolism, an systemic, renal, or skeletal Ca homeostasis are incompletely understood. We propose that the increasingly-recognized, distinctive syndrome of familial benign hypercalcemia (FBH, or hypocalciuric hypercalcemia) provides a unique opportunity to probe the mechanisms of calcium homeostasis. The FBH syndrome includes lifelong, dominantly-inherited hypercalcemia, enhanced renal tubular reabsorption of Ca-non-suppressed but generally not elevated parathyroid hormone (PTH) secretion, usually normal parathyroid histology, and failure of subtotal parathyroidectomy to normalize serum Ca. Affected persons are frequently misdiagnosed as having primary hyperparathyroidism and receive inappropriate treatment. The central hypothesis of the proposed research is that FBH results from a single autosomal genetic mutation that simultaneously affects function of the parathyroid glands, kidney, and possibly other tissues. The principal investigator has assembled over the last 12 years a large clinical resource that forms the basis for the current grant and this renewal application; thirty families and more that 150 affected persons have been ascertained. We have obtained DNA and transformed lymphoblasts from 4 entire families and nearly completed a fifth. We propose 1) to complete DNA sampling and lymphoblast transformation for at least 11 large families plus selected members of all others; 2) to conduct candidate gene and general linkage searches for the chromosomal location of the FBH locus; 3) having achieved linkage, to refine the mapping of the locus and search for locus and allelic heterogeneity, looking systematically for small deletions of rearrangements in the mapped region; and 4) in parallel with the genetic studies, to determine in cultured dermal fibroblasts from affected and normal persons if there are functional differences in growth, cellular Ca metabolism, or PTH receptor expression and physiology that might aid the search for the mutated gene. The PI has just completed an NIH-supported sabbatical leave in Dr. Ray White's group at the University of Utah where he learned genetic linkage analysis and began the search. The techniques, resources, and expertise needed to conduct the proposed studies are in place in the principal investigator's laboratory or those of his collaborators, including: analysis of restriction fragment length and variable number tandem repeat polymorphisms; use of the polymerase chain reaction to detect multiallelic short repeat sequences; creation and mapping of new DNA markers when needed to refine localization; cell culture; cytosolic ionized Ca determination by various methods; and PTH receptor assays. These unique systematic studies should lead to chromosomal localization of the gene mutated in FBH, and set the stage for its later cloning. Furthermore, we believe this research ultimately will improve general knowledge of genetic control in normal and abnormal parathyroid and renal Ca metabolism.